Path of Least Resistance

With a wave of new HIV drug approvals expected over the next year or so, we may finally see a dramatic reduction in the number of people with HIV who find themselves "unable to construct a viable regimen"; the classic definition of the so-called "salvage" patient who has developed resistance to nearly every available antiretroviral treatment option.

In other words, the near decade-long salvage crisis for highly treatment-experienced patients may finally be ending. Of course, some will still develop resistance to every new drug that comes to market, though -- hopefully -- those patients will be few.

But anticipation of this welcome accomplishment has also raised a perplexing question from drug developers: If there are no salvage patients then how can we develop the next salvage drug -- or any new HIV drug, for that matter?

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The last few HIV drugs to be approved were tested in clinical trials that compared a standard, best-available treatment regimen (optimized background therapy) with the standard treatment plus the experimental drug. At the end of 24 weeks, if viral load reductions were greater in the group that received the test medication than in the comparison group then the new drug was a winner. When the best available background regimens could suppress HIV in perhaps 25% of highly treatment-experienced trial subjects, it was not hard to demonstrate the value of a new drug that could double that rate.

But if this new wave of drugs now or soon-to-become available for use in standard regimens can effectively suppress viral load in 80%-90% of highly treatment-experienced patients, then how can a clinical trial show that adding an experimental drug contributes any measurable benefit? If we are wedded to the salvage trial design, nervous drug makers are asking, how can we prove that a new drug works?

The "add-on" salvage trial design was an efficient and successful drug development strategy for industry. Companies scrambled to develop salvage drugs, not only because there was a critical need in the US and Europe, but also because the six-month salvage study offered a fast path to accelerated approval -- and that path was well understood. The FDA had made it clear what needed to be done to get a salvage drug approved. As a bonus incentive, accelerated approval also meant that a new drug could start earning revenue a critical six months to a year sooner than would be possible under traditional approval.

But with the salvage study population drying up, the industry is becoming nervous about the feasibility of testing a new generation of drugs. What will the FDA demand? Can new drugs be studied in treatment-naive populations? (That is where the greatest unmet medical need has now shifted to.) Will additional safety hurdles have to be met before trials in treatment-naive patients are permitted? Will future trials need to be much larger or run for several years longer than they have in the past?

Drug companies like to start planning for possible drug development pathways many years in advance to help them anticipate the potential risks and rewards of investing in a new drug. Decisions are being made today about drugs that may not come to market before 2012. Unanswered questions about the regulatory environment tend to make investment decisions seem more risky.

We are entering a period of uncertainty about how the next generation of HIV drugs can be developed. Until that uncertainty is resolved, pharmaceutical makers may become cautious about starting up major new HIV drug development programs. That would be bad for the millions of people with HIV in the world who have yet to go on treatment and for the tens-of-thousands who will inevitably need to switch to a better treatment -- including present and future salvage patients.

The FDA needs make it clear to industry and advocates: What is the best way to develop new HIV drugs in the post-salvage era? What is the new path of least resistance?

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